Pyruvate is a three-carbon (triose) ketoacid that is produced in biological systems in the end stages of glycolysis, a product of sugar metabolism. It is also a breakdown product of certain amino acids (alanine, glycine, cysteine, serine). Pyruvate can be reduced to lactate in the cytoplasm, a fermentative event in mammalian cells, or oxidatively decarboxylated to acetyl CoA in the mitochondrion.
There are known in the art a number of pyruvate derivatives. It has been suggested that pyruvate and certain pyruvate derivatives may have utility in treating certain disorders and promoting health. For example, pyruvate is sold as a dietary supplement for use in promoting weight loss and enhancing energy. It has also been suggested as a therapeutic intervention for clinical management of myocardial insufficiency (Mallet, R. T., 2000, Proc. Soc. Exp. Biol. Med. 223(2): 136-148) and to prevent the adverse effects of myocardial ischemia (U.S. Pat. No. 5,294,641). U.S. Pat. Nos. 5,075,210 and 4,988,245 describe the use of pyruvate or pyruvate salts as a component in a cardioplegic solution and in preservation solutions (perfusion fluids) for heart allografts before transplantation. U.S. Pat. No. 5,395,822 describes the use of certain pyruvate salts to protect against neuronal degeneration as a consequence of ischemia.
U.S. Pat. No. 6,086,789 describes certain pyruvate derivatives as useful for dermatologic indications as well as for treating diabetic ketosis, myocardial ischemia, injured organs and hypercholesterolemia. Specifically, it ascribes these activities to various esters of pyruvate, including polyol-pyruvate esters, pyruvate thioesters, glycerol-pyruvate esters, and dihydroxyacetone-pyruvate ester. Related U.S. Pat. No. 5,968,727 describes the use of pyruvate thiolesters, such as cysteine, methionine and homocysteine, and glycerol pyruvate esters and dihydroxyacetone-pyruvate esters, in organ preservation solutions and for treating ischemia. Similarly, certain pyruvate and pyruvyl amino acid conjugates have been suggested for use in diabetes (e.g., U.S. Pat. Nos. 5,047,427 and 5,256,697).
It has, however, remained desired to provide new therapies for conditions characterized by oxidative stress, and particularly, for providing neuroprotection in the event of cerebral ischemia; especially desired are agents that are effective even if first administered after a significant period of time (e.g., about 5 or more hours) following an ischemic insult.